The present invention relates to new compounds of 7-oxo-2,3,7,14-tetrahydro-1H-benzo[b]pyrano[3,2-h]acridin carboxylate and to pharmaceutical compositions containing them.
The compounds of the invention are derivatives of acronycine which is an alkaloid having anti-tumour properties that have been demonstrated in experimental models (J. Pharm. Sci. 1966, 55 (8), 758-768). Despite a broad spectrum of activity, however, acronycine is sparingly soluble, which limits its bioavailability and its use in pharmaceutical compositions for administration by injection.
Various modifications have been made to this molecule, such as those described in J. Med. Chem., 1996, 39, 4762-4766, and have made it possible to resolve some of the difficulties associated with the problem of the solubility of these compounds. Nevertheless, anti-cancer therapy requirements call for the constant development of new anti-tumour agents with the aim of obtaining medicaments that are simultaneously more active and better tolerated. In particular, solid tumours pose a major problem in anti-cancer chemotherapy owing to their intrinsic and/or acquired resistance to existing products.
In addition to the fact that the compounds of the invention are new, they have a surprising in vivo and in vitro activity that is superior to that observed hitherto. Moreover, the compounds have valuable properties in respect of solubility, making them suitable for administration of the compounds in liquid form. The compounds discovered by the Applicant thus have anti-tumour properties that make them especially useful in the treatment of cancer, especially of solid tumours.
More especially, the present invention relates to compounds of formula (I): 
wherein:
X and Y, which may be identical or different, each independently of the other represents a group selected from a hydrogen atom, a halogen atom, a hydroxy group, a mercapto group, a cyano group, a nitro group, a linear or branched (C1-C6)alkyl group, a linear or branched (C1-C6)alkoxy group, a trihalo-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, and an amino group (optionally substituted by one or two identical or different linear or branched (C1-C6)alkyl groups which may themselves be substituted by a linear or branched (C1-C6)alkoxy group or by a group of formula xe2x80x94NR7R8 wherein R7 and R8, which may be identical or different, each independently of the other represents a hydrogen atom, a linear or branched (C1-C6)alkyl group, an aryl group or an aryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched), or X and Y together form a methylenedioxy or ethylenedioxy group, it being understood that the substituents X and Y may be present on one or the other of the two adjacent benzene rings,
R1 represents a hydrogen atom or a linear or branched (C1-C6)alkyl group,
R2 represents:
a hydrogen atom,
a hydroxy group,
a linear or branched (C1-C6)alkyl group,
a linear or branched (C1-C6)alkoxy group optionally substituted by a group selected from:
a group of formula NR9R10 wherein R9 and R10, which may be identical or different, each independently of the other represents a hydrogen atom, a linear or branched (C1-C6)alkyl group, or a linear or branched (C1-C6)hydroxyalkyl group, and
a saturated or unsaturated monocyclic or bicyclic heterocycle having from 5 to 7 ring members containing one or two hetero atoms selected from oxygen, nitrogen and sulphur,
a linear or branched (C1-C6)alkylcarbonyloxy group, or
an amino group optionally substituted by:
one or two, identical or different, linear or branched (C1-C6)alkyl groups, aryl groups or aryl-(C1-C6)alkyl groups in which the alkyl moiety is linear or branched,
a linear or branched (C1-C6)alkylcarbonyl group optionally substituted by a group xe2x80x94NR7R8 wherein R7 and R8 are as defined hereinbefore,
a group of formula xe2x80x94R11xe2x80x94NR9R10, wherein R11 represents a linear or branched (C1-C6)alkylene group, and R9 and R10, which may be identical or different, each independently of the other represents a hydrogen atom, a linear or branched (C1-C6)alkyl group, or a linear or branched (C1-C6)hydroxyalkyl group,
a linear or branched (C1-C6)alkylene group, substituted by a saturated or unsaturated, monocyclic or bicyclic heterocycle having from 5 to 7 ring members containing one or two hetero atoms selected from oxygen, nitrogen and sulphur, or
by a group of formula xe2x80x94R11xe2x80x94COxe2x80x94R12 wherein R11, is as defined hereinbefore, and R12 represents a hydroxy group or a linear or branched (C1-C6)alkoxy group,
R3 and R4, which may be identical or different, each independently of the other represents a hydrogen atom or a linear or branched (C1-C6)alkyl group,
R5 and/or R6 represent(s) a group of formula xe2x80x94Oxe2x80x94COxe2x80x94Uxe2x80x94V wherein:
U represents a linear or branched (C1-C8)alkylene chain, optionally substituted by one or more identical or different groups selected from aryl, hydroxy and linear or branched (C1-C6)alkoxy,
V represents a group selected from:
carboxy,
xe2x80x94CO2R13 wherein R13 represents a linear or branched (C1-C6)alkyl group (optionally substituted by one or more hydroxy groups), an aryl group or an aryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched,
hydroxy,
linear or branched (C1-C6)alkoxy,
xe2x80x94NR7R8 wherein R7 and R8, which may be identical or different, are as defined hereinbefore,
xe2x80x94NR7xe2x80x94CO2R13 wherein R7 and R13 are as defined hereinbefore,
xe2x80x94NR7xe2x80x94COR13 wherein R7 and R13 are as defined hereinbefore,
xe2x80x94COR13 wherein R13 is as defined hereinbefore, and
xe2x80x94COxe2x80x94NR7R8 wherein R7 and R8, which may be identical or different, are as defined hereinbefore,
xe2x80x83and when only one of the two groups R5 and R6 represents a group of formula xe2x80x94Oxe2x80x94COxe2x80x94Uxe2x80x94V, then the other of the said R5 and R6 groups represents a group Z selected from:
hydroxy,
linear or branched (C1-C6)alkoxy,
linear or branched (C1-C6)alkylcarbonyloxy,
arylcarbonyloxy,
aryl-(C1-C6)alkylcarbonyloxy in which the alkyl moiety is linear or branched, and
amino optionally substituted by one or two identical or different linear or branched (C1-C6)alkyl groups,
their isomers, N-oxides, and addition salts thereof with a pharmaceutically acceptable acid or base.
xe2x80x9cArylxe2x80x9d is understood to mean a phenyl or naphthyl group, optionally containing one or more identical or different substituents selected from hydroxy, halogen, carboxy, nitro, amino, (C1-C6)alkylamino or di-(C1-C6)alkylamino in which the(each) alkyl moiety is linear or branched, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)acyl, and linear or branched (C1-C6)alkylcarbonyloxy.
Among the pharmaceutically acceptable acids there may be mentioned by way of non-limiting example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulphonic acid, camphoric acid, lysine, etc.
Among the pharmaceutically acceptable bases there may be mentioned by way of non-limiting example sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc.
The preferred R3 and R4 substituents according to the invention are linear or branched (C1-C6)alkyl groups in which R3 and R4 may be identical or different. R3 and R4 are preferably identical and each represents a methyl group.
The preferred R2 substituents according to the invention are linear or branched (C1-C6)alkoxy groups, or amino groups optionally substituted by one or two substituents as defined for formula (I).
According to an advantageous embodiment, the preferred compounds of the invention are those wherein R5 represents a group of formula xe2x80x94Oxe2x80x94COxe2x80x94Uxe2x80x94V wherein U and V are as defined for formula (I), and R6 represents a group Z as defined for formula (I).
According to another advantageous embodiment, the preferred compounds of the invention are those wherein R6 and R5 each represents an identical group of formula xe2x80x94Oxe2x80x94COxe2x80x94Uxe2x80x94V wherein U and V are as defined for formula (I).
The preferred R5 substituent according to the invention is the group of formula xe2x80x94Oxe2x80x94COxe2x80x94Uxe2x80x94V wherein U represents a linear (C1-C4)alkylene chain and V represents a group selected from carboxy, xe2x80x94NR7R8, xe2x80x94NR7xe2x80x94CO2R13 and xe2x80x94NR7xe2x80x94COR13 wherein R7, R8 and R13, which may be identical or different, represent a hydrogen atom or a linear or branched (C1-C4)alkyl group.
The preferred R6 substituent according to the invention is the linear or branched (C1-C6)alkylcarbonyloxy group.
The preferred compounds of the invention are:
(xc2x1)-cis-4-{[1-(acetyloxy)-6-methoxy-3,3,14-trimethyl-7-oxo-2,3,7,14-tetrahydro-1H-benzo[b]pyrano[3,2-h]acridin-2-yl]oxy }-4-oxobutanoic acid,
(xc2x1)-cis-4-({1-[(3-carboxypropanoyl)oxy]-6-methoxy-3,3,14-trimethyl-7-oxo-2,3,7,14-tetrahydro-1H-benzo[b]pyrano[3,2-h]acridin-2-yl }oxy)-4-oxobutanoic acid,
(xc2x1)-cis-5-{[1-(acetyloxy)-6-methoxy-3,3,14-trimethyl-7-oxo-2,3,7,14-tetrahydro-1H-benzo[b]pyrano[3,2-h]acridin-2-yl]oxy}-5-oxopentanoic acid,
cis-[1-(acetyloxy)-6-methoxy-3,3,14-trimethyl-7-oxo-2,3,7,14-tetrahydro-1H-benzo[b]pyrano[3,2-h]acridin-2-yl](dimethylamino)acetate, and
cis-[1-(acetyloxy)-6-methoxy-3,3,14-trimethyl-7-oxo-2,3,7,14-tetrahydro-1H-benzo[b]pyrano[3,2-h]acridin-2-yl]4-(dimethylamino)butanoate.
The isomers, N-oxides, and addition salts with a pharmaceutically acceptable acid or base of the preferred compounds are an integral part of the invention.
The present invention relates also to a process for the preparation of compounds of formula (I), characterised in that:
either a 3-amino-2-naphthalenecarboxylic acid compound (II): 
xe2x80x83wherein X and Y are as defined for formula (I), is reacted with a phloroglucinol compound of formula (III): 
xe2x80x83wherein R represents a hydrogen atom, a hydroxy group or a linear or branched (C1-C6)alkyl group, to yield the compounds of formula (IV): 
xe2x80x83wherein X, Y and R are as defined hereinbefore, which are then treated under basic conditions in an aprotic solvent, such as, for example, dimethylformamide, with an alkyne of formula (V): 
xe2x80x83wherein Hal represents a halogen atom and R3 and R4 are as defined for formula (I), to yield the compounds of formula (VI): 
xe2x80x83wherein X, Y, R, R3 and R4 are as defined hereinbefore,
xe2x80x83or a 3-halo-2-naphthalenecarboxylic acid compound of formula (VII): 
xe2x80x83wherein X and Y are as defined for formula (I) and Hal represents a halogen atom, such as chlorine or bromine, is reacted with an amino-chromene compound of formula (VIII): 
xe2x80x83wherein R3 and R4 are as defined for formula (I) and R is as defined hereinbefore, also to yield the compounds of formula (VI): 
xe2x80x83wherein X, Y, R, R3 and R4 are as defined hereinbefore, the nitrogen atom of which compounds of formula (VI) is optionally substituted, by the action of an alkyl halide or a dialkyl sulphate in the presence of a deprotonating agent, such as sodium hydride, in an aprotic polar solvent, to yield the compounds of formula (IX): 
xe2x80x83wherein X, Y, R, R3 and R4 are as defined hereinbefore, and Rxe2x80x21 represents a linear or branched (C1-C6)alkyl group, which compounds of formula (IX) are subjected to the action of an alkylating agent, such as a dialkyl sulphate, or of an acylating agent, to yield the compounds of formula (X): 
xe2x80x83wherein X, Y, Rxe2x80x21, R3 and R4 are as defined hereinbefore and Rxe2x80x22 represents an alkoxy group (optionally substituted by a group of formula NR9R10 wherein R9 and R10 are as defined for formula (I)), or a linear or branched (C1-C6)alkylcarbonyloxy group, which compound of formula (X), when Rxe2x80x22 represents an alkoxy group for example, is treated with a compound of formula (XI):
HNRaRbxe2x80x83xe2x80x83(XI)
xe2x80x83wherein Ra represents a hydrogen atom, a linear or branched (C1-C6)alkyl group, an aryl group, or an aryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, and Rb represents a hydrogen atom, a linear or branched (C1-C6)alkyl group, an aryl group, an aryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, a group of formula xe2x80x94R11xe2x80x94NR9R10 wherein R11, R10 and R9 are as defined for formula (I), a linear or branched (C1-C6)alkylcarbonyl group in which the alkyl moiety is optionally substituted by a group NR7R8 as defined for formula (I), a heterocycloalkylene group (the terms xe2x80x9calkylenexe2x80x9d and xe2x80x9cheterocyclexe2x80x9d being as defined for formula (I)) or a group of formula xe2x80x94R11xe2x80x94COxe2x80x94R12 wherein R11 and R12 are as defined for formula (I), to yield the compounds of formula (XII): 
xe2x80x83wherein X, Y, Rxe2x80x21, R3, R4, Ra and Rb are as defined hereinbefore, the totality of the compounds of formulae (VI), (IX), (X) and (XII) constituting the compounds of formula (XIII): 
xe2x80x83wherein X, Y, R1, R2, R3 and R4 are as defined in the general definition of formula (I), which compounds of formula (XIII) are subjected
a)  either to the action of osmium tetroxide in a polar medium and in the presence of 4-methylmorpholine-N-oxide, to yield the compounds of formulae (XIV/a) and (XIV/b): 
xe2x80x83wherein X, Y, R1, R2, R3 and R4 are as defined hereinbefore, it also being possible for the compounds of formulae (XIV/a) and (XIVb) to be obtained separately by chiral synthesis and especially by asymmetric cis dihydroxylation starting from compound (XIII) using chiral ligands of the pyridine or phthalazine type bisubstituted by Cinchona alkaloids, such as dihydroquinine and its dextrorotatory diastereoisomer, dihydroquinidine,
b)  or to the action of potassium permanganate in a polar medium, to yield the compounds of formula (XV): 
xe2x80x83wherein X, Y, R1, R2, R3 and R4 are as defined hereinbefore, which compounds of formula (XV) are subjected to reductive conditions in the presence of NaBH4 for example, to yield the compounds of formula (XIV/c): 
xe2x80x83wherein X, Y, R1, R2, R3 and R4 are as defined hereinbefore, the totality of the compounds of formulae (XIV/a), (XIV/b) and (XIV/c) constituting the compounds of formula (XIV): 
xe2x80x83wherein X, Y, R1, R2, R3 and R4 are as defined hereinbefore, which compounds of formula (XIV) are subjected:
either to the action of an alcohol of formula R20xe2x80x94OH wherein R20 represents a linear or branched (C1-C6)alkyl group, to yield the compounds of formula (XVI/a): 
xe2x80x83wherein X, Y, R1, R2, R3, R4 and R20 are as defined hereinbefore, the alcohol function of which compounds of formula (XVI/a) is esterified in the presence of a compound of formula 
xe2x80x83wherein U and V are as defined for formula (I) and W represents a leaving group, to yield the compounds of formula (I/a), a particular case of the compounds of formula (I): 
xe2x80x83wherein X, Y, R1, R2, R3, R4, R20, U and V are as defined hereinbefore,
or to the action of an alkyl iodide of formula Rxe2x80x220-I wherein Rxe2x80x220 represents a linear or branched (C1-C6)alkyl group, in the presence of a silver salt, to yield the compounds of formula (XVI/b): 
xe2x80x83a particular case of the compounds of formula (I), wherein X, Y, R1, R2, R3, R4 and Rxe2x80x220 are as defined hereinbefore, the alcohol function of which compounds of formula (XVI/b) is esterified in the presence of a compound of formula 
xe2x80x83as defined hereinbefore, to yield the compounds of formula (I/b): 
xe2x80x83a particular case of the compounds of formula (I), wherein X, Y, R1, R2, R3, R4, Rxe2x80x220, U and V are as defined hereinbefore,
or to the direct action of a compound of formula 
xe2x80x83as defined hereinbefore, in the presence of a base, such as triethylamine or 4-dimethylaminopyridine, in order to obtain the compounds of formula (I/c), a particular case of the compounds of formula (I): 
xe2x80x83wherein X, Y, R1, R2, R3, R4, U and V are as defined hereinbefore, which compound of formula (I/c) may be subjected again, under the same operating conditions, to the action of an anhydride of formula (R30CO)2O wherein R30 represents a linear or branched (C1-C6)alkyl group, an aryl group or an aryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, to yield the compounds of formula (I/d): 
xe2x80x83wherein X, Y, R1, R2, R3, R4, R30, U and V are as defined hereinbefore, or which compound of formula (I/c) may be treated again with a compound of formula 
xe2x80x83as defined hereinbefore, to yield the compounds of formula (I/e), a particular case of the compounds of formula (I): 
xe2x80x83wherein X, Y, R1, R2, R3, R4, U and V are as defined for formula (I), it being understood that the two U groups and the two V groups may each be identical or different,
c)  or to the action of a peracid, such as m-chloroperbenzoic acid, to yield the compound of formula (XVII): 
xe2x80x83wherein X, Y, R1, R2, R3 and R4 are as defined hereinbefore, which compound of formula (XVII) is optionally treated with ammoniac or a primary or secondary amine to yield the compounds of formula (XVIII/a) and/or (XVIII/b) depending upon the nature of the reagents: 
xe2x80x83wherein X, Y, R1, R2, R3 and R4 are as defined hereinbefore, and Rc and Rd represent a hydrogen atom or a linear or branched (C1-C6)alkyl group, which compounds of formulae (XVIII/a) and (XVIII/b) are treated with a compound of formula 
xe2x80x83as defined hereinbefore, to yield the compounds of formulae (I/f) and (I/g), respectively, particular cases of the compounds of formula (I): 
xe2x80x83wherein X, Y, R1, R2, R3, R4, Rc, Rd, U and V are as defined hereinbefore,
which compounds (I/a) to (I/g) constitute the totality of the compounds of the invention, which are purified, if necessary, according to a conventional purification technique, may be separated, if desired, into their various isomers according to a conventional separation technique, and which are converted, if desired, into N-oxides thereof and, where appropriate, into addition salts thereof with a pharmaceutically acceptable acid or base.
The compounds of formulae (II), (III), (V), (VII), (VIII) and (XI) are either commercial compounds or are obtained according to conventional methods of organic synthesis. The compounds of formula (VIII), for example, are obtained according to the conditions described in Chem. Ber. 1978, 191, 439. The condensation reaction between the compounds of formula (VII) and the compounds of formula (VIII) is described, for example, in the journal Heterocycles, 1992, 34(4), 799-806.
The compounds of formula (I) have especially valuable anti-tumour properties. They have excellent in vitro cytotoxicity on cell lines from murine and human tumours because of specific blocking of the cell cycle, and they have in vivo activity, in mice, on murine and human transplantable tumours. The characteristic properties of those compounds enables them to be used therapeutically as anti-tumour agents.
The present invention relates also to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I), its optical isomers, N-oxides or an addition salt thereof with a pharmaceutically acceptable acid or base, alone or in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers.
Among the pharmaceutical compositions according to the invention, special mention is made of those that are suitable for oral, parenteral (intravenous, intramuscular or sub-cutaneous), per- or trans-cutaneous, nasal, rectal, perlingual, ocular or respiratory administration, and especially tablets or dragxc3xa9es, sublingual tablets, gelatin capsules, capsules, suppositories, creams, ointments, dermal gels, injectable or drinkable preparations, aerosols, eye or nose drops, etc.
The useful dosage varies according to the age and weight of the patient, the route of administration, the nature and severity of the disorder and whether any associated treatments are being taken, and ranges from 0.5 mg to 500 mg in one or more administrations per day.